Disposition of a new rate-controlled formulation of prazosin in the treatment of hypertension during pregnancy: transplacental passage of prazosin.

Prazosin (PRZ) in conventional tablet form (P-CT) has the disadvantages of a relatively short terminal half-life, a slight solubility in water and the well-recognized adverse effect of symptomatic orthostatic hypotension. The pharmacokinetic study of a new rate-controlled formulation of prazosin (Prazosin-Gastrointestinal System: P-GS) was performed in 9 pregnant women during the third trimester of pregnancy. Patients had persistent elevation of blood pressure. The subjects gave their informed consent for oral administration of 1 daily dose of 5 mg P-GS at 8 a.m. A first analysis period on day 1 enabled definition of the initial pharmacokinetic behavior of the drug, while the aim of a second was to evaluate its fate at plateau. The clinical course of both mother and fetus was subsequently monitored. This was an open, non-randomized study, each patient serving as her own control. For 3 patients, we aimed to determine the possible transplacental passage of PRZ at delivery. PRZ levels were measured by HPLC and data were analysed by noncompartmental linear pharmacokinetic methods. The data show: (i) P-GS was well tolerated by all patients and there were no significant changes in fetal heart rate during the study. (ii) A significant decrease in diastolic blood pressure was observed after the 36th hour following the first dose of P-GS while a reduction in systolic blood pressure was observed on day 4. (iii) An approximated relative bioavailability (f'P-GS) of 36.5% was calculated. P-GS appears to have a lower bioavailability than P-CT in women of similar gestational age. (iv) Both Cmax and AUC0-->infinity are significantly increased at plateau. Further, terminal half-life is increased with regard to the value determined with P-CT. No accumulation of PRZ was noted at steady-state. (v) P-GS is an example of an oral zero-order absorption product that offers one approach to control and improve the outcome of hypertensive therapy during pregnancy. This treatment could represent an alternative to methyldopa as a first treatment of pregnancy-associated hypertension. (vi) There is a slight transplacental passage of the drug (of the order of 10-20%).

[Weak transplacental passage of prazosin (Alpress) during the third trimester of pregnancy. 3 cases]. / Faible passage transplacentaire de la prazosine (Alpress) au cours du troisième trimestre de la grossesse. A propos de trois cas.

Prazosin is a selective peripheral alpha 1-adrenoceptor antagonist used in the treatment of hypertension and heart failure. This drug has the disadvantage of relatively short terminal half-life (of the order of 2 to 3 hours); its wide use has been limited by the number of daily administrations. Recently, a new formulation of prazosin has been commercialized i.e., prazosin-gastrointestinal therapeutic system (P-GITS) given once daily in doses of either 2.5 or 5.0 mg (i.e., Alpress). The potential suitability of this controlled-release system as treatment of hypertension during pregnancy seems important. However, the possible transplacental passage of PRZ was unknown. We aimed to study this phenomenon in three pregnant women given a once daily 5 mg dose of P-GITS during the third trimester of pregnancy. There is a slight transplancental passage of prazosin i.e., of the order of 10 to 20% of the maternal concentration level determined at the same time. Concerning neonatal outcome, no problems were noted and the babies left the hospital in good health. Prazosin-GITS offers a new approach to control and improve the outcome of hypertensive therapy during pregnancy.

Transplacental passage of vancomycin during the second trimester of pregnancy.

Pharmacokinetics and drug monitoring of vancomycin were studied at mid-pregnancy in a patient with chorioamnionitis due to Streptococcus agalactiae. The terminal half-life remained in the normal range (4-6 hours) because of an equivalent increase in both volume of distribution and total plasma clearance. Transplacental passage of the drug was observed. Monitoring is mandatory for prolonged vancomycin therapy, and the results should be available within 24 hours. The therapeutic regimen of 15-20 mg/kg every 12 hours was sufficient for this patient's chorioamnionitis. Serum drug levels and renal function should be measured before increasing the vancomycin dosage.